The behavioral changes produced by amphetamine and related CNS stimulants (methyl-phenidate and pipadrol) are thought to be mediated through the release of dopamine (DA) from specific sites in the brain. This hypothesis is consistent with the observation that amphetamine can increase the rate of DA turnover in the striatum. We propose to study the mechanism of the stimulation of DA turnover in-vitro using striatal slices and synaptosomes. We have found that amphetamine can stimulate the synthesis and release of DA in these preparations at low concentrations, and that both effects are markedly enhanced by the addition of calcium to the medium. Consequently, we will try to determine 1) the nature of the amphetamine-calcium interaction; 2) how this interaction leads to the stimulation of tyrosine hydroxylase activity; and 3) the role of calcium in the amphetamine-induced release of DA. Since the effects of amphetamine on tyrosine hydroxylase activity in striatal slices appears to be similar to that of depolarizing agents, we will compare the effects of amphetamine with veratridine and high potassium concentration on the activity of the enzyme in this preparation. We will also characterize the effects of methylphenidate and pipadrol on DA synthesis and release, since although these compounds are CNS stimulants, they appear to interact with DA nerve terminals in a different way from amphetamine. Finally, we will study the role of DA synthesis and the transport of amphetamine into DA neurons on the amphetamine-induced stimulation of locomotor activity and stereotyped behavior. These studies will be of value in defining the molecular mechanisms involved in the behavioral effects of amphetamine and analogous CNS stimulants and in understanding how the balance between the synthesis and release of neurotransmitters is maintained under normal and pathological conditions.